New cancer therapies with novel mechanisms-of-action (MOA) are needed. Current therapies often have limited efficacy when used as single agents, so in practice are used in combination for maximal effect. Novel agents should ideally lack cross-resistance with approved therapies, and should have multiple complementary MOA1-4. Engineered viruses have been developed for cancer treatment using different approaches, including “gene therapy” (therapeutic transgene transfer in a replication-incompetent virus)5-7 and cancer vaccines (expression of tumor antigens, co-stimulatory molecules and/or cytokines)8-10. However, gene therapy has failed to date in patients due to inefficient delivery to sufficient numbers of cancer cells locally and systemically. In contrast, virus-based cancer vaccines have been limited by tumor immune evasion and exclusive reliance on host factors for efficacy in patients with advanced bulky cancers. Immune evasion is most likely with vaccine approaches that rely on the expression of a single tumor antigen and/or a single cytokine. Broad-based therapeutic cancer vaccines are needed to express multiple tumor antigens, cytokines, immune cell recruitment and activation, and immune response danger signals.
In contrast, oncolytic viruses were developed to take advantage of viruses' natural ability to infect, multiply within and subsequently lyse cancer cells11-14. First-generation oncolytic viruses were inherently cancer-selective (e.g. reovirus15-16, VSV17-18) whereas second-generation agents were engineered for cancer selectivity (e.g. adenovirus19-20 and herpes simplex virus21-22 deletion mutants). Clinical trial data with these agents demonstrated safety and cancer selectivity, but therapeutic potency was limited both after direct intratumoral or intravenous injection23; systemic spread and/or reproducible delivery to distant tumors were limited, however. Systemic anti-cancer potency and blood-borne delivery to metastatic tumors therefore had to be improved.
Given both the potential and the limitations with each of these three individual virus-based approaches, we asked whether it was possible to combine and optimize the best attributes of each into a single therapeutic agent. Targeted and armed oncolytic poxviruses have the potential to do so. JX-594 is a 3rd-generation oncolytic poxvirus therapeutic designed to have three complementary MOA including: 1) direct replication-mediated oncolysis, and 2) active cancer vaccination. JX-594 is a Wyeth vaccinia virus vaccine-derived oncolytic with disruption of the viral thymidine kinase gene and expression of the human granulocyte-monocyte colony stimulating factor (hGM-CSF) and β-galactosidase transgenes under control of the synthetic early-late and p7.5 promoters, respectively24. Vaccinia was used as the virus backbone because of its stability in blood for blood-borne delivery to tumors25. JX-594 is designed to induce cancer vaccination through simultaneous cancer cell lysis and endogenous tumor antigen release, expression of hGM-CSF to support antigen-presenting cell activation, recruitment of immune effector cells and proinflammatory cytokine induction. Clearance of vaccinia itself is primarily via infected cell clearance through cell-mediated immune mechanisms.
The inventors have now discovered a new method of treatment of cancer using oncolytic viruses to address the need in the art for new cancer therapies.